Circulating cholesterol is carried by two major cholesterol carriers, low density lipoproteins (LDL), and high density lipoproteins (HDL). LDL is believed to be responsible for the delivery of cholesterol from the liver (where it is synthesized or obtained from dietary sources) to extrahepatic tissues in the body. It is believed that plasma HDL particles play a major role in cholesterol regulation, acting as scavengers of tissue cholesterol.
Atherosclerosis is a slowly progressive disease characterized by the accumulation of cholesterol within the arterial wall. Compelling evidence indicates that lipids deposited in atherosclerotic lesions are derived primarily from plasma LDL; thus, LDLs have popularly become known as the “bad” cholesterol. In contrast, HDL serum levels correlate inversely with coronary heart disease—indeed, high serum levels of HDL are regarded as a negative risk factor. Each HDL particle contains at least one copy of ApoA-I. It is hypothesized that high levels of plasma HDL are not only protective against coronary artery disease, but can actually induce regression of atherosclerotic plaques (See, Badimon et al., 1992, Circulation 86 (Suppl. III):86-94). Thus, HDL has popularly become known as the “good” cholesterol.
A number of treatments are currently available for lowering serum cholesterol and triglycerides (See, Brown & Goldstein, In, The Pharmacological Basis of Therapeutics, 8th Ed., Goodman & Gilman, Pergamon Press, N.Y., 1990, Ch. 36, pp. 874-896). However, each has its own drawbacks and limitations in terms of efficacy, side-effects and qualifying patient population. Antihyperlipidemic agents such as statins (e.g. MEVACOR®, LIPITOR®) can cause life-threatening side effects, such as rhabdomyolysis. In addition, these treatments can be very expensive. The use of human ApoA-I as a treatment has the disadvantages of limited supply and the possibility of disease transmission via blood born pathogens.
There is a need to develop safer and cost effective treatments for lowering serum cholesterol, increasing HDL serum levels, preventing coronary heart diseases and/or treating existing disease, especially atherosclerosis.